Process of preparing arylaminomethylenemalonates



Patented May 12, 1953 spa n- PROCESS OF PREPARING ARYLAMINO-METHYLENEMALONATES Samuel A. (Hickman, Easton,

General Aniline & Film Corporation,

Pa., assignor to New York,

N. Y., a. corporation of Delaware No Drawing.

This invention relates to an improved process of preparingarylaminomethylenemalonates.'

-It is known that arylaminomethylenemalonates undergo thermalcyclization to yield the corresponding nuclear substituted l-hydroziyquinolineswhich are convertedto the l -chloroquino1ines-;followed bytreatment with various amines toyield commerciallyimportant antimalarial drugs, i. e., Chloroquine and Came Heretofore, the synthesis ofthe arylaminomethylenemalonates has not lent itself t any., one generalmethod anddependedfor itssuc'cess' on (1) the ability to secure thenecessaryinter j mediates from the activated ester, or t'z") the;ability to avoid side reactions which very often complicated operationsand led toimpuriti'es'l" The arylaminomethylenemalonates underconsideration are characterized by the following formulae: 6 In VNHCH=C(COOR)2U 7 R1 p wherein R represents a lower alkyl group, e; g.,'methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the" like,'andfRf represents a nuclear s'u-bstitu'ent, such as an alkylfif thesame vali'ie a's R, j alkylamino'," an alkox'y', e1'fg1,"metho'$ y,etlio propox'y'; b'utoxy, etc., or a halogen, such ashl'o rin e,bromine, or iodine. It is to be noted that the compound'designated 1(1)is also depicted as being in tautomeric equilibrium with" 'the' conesponding' anil' (2) as shown. 'Both' types of coin pounds, i.'e.,' (1)-and (ZY'undergO the thermal cyclization referred to above. Theliterature (Annalen 297, '77 [1897] JACS 68,1204 [1946]; and OrganicSyntheses, vol. 28, '38-'41 [1948]) reports the synthesis of'compo mds;of the type (1) or (2) by thereaction'ofaromatid amines withethoxymethylenemalonicester, ac cording tothe following equation:

'- -@nnaaimoQoredwoam) uee-ozkowoocrmtz Application December 31, 1951,,S erial'No. 264,352

Claims. (01. 260-471) wherein R1 has the same value as above.

' yield have been noted, especially in manufactur- The use of the abovereaction for large scale operations is attendant with variousdiificulties, one of which is the limited availability of theethoxymethylenemalonic ester. The synthesis of the latter compoundproceeds at best in 50-60% yields based on malonic ester and 44-53%yields basedon ethyl orthoformate (Organic Syntheses, vol. 28, 38-41.[l948]). The reaction times and conditions are critical and widefluctuations in ing scale operations. Furthermore, the use of ethylethoxymethylenemalonate is also objectionable for the additional reasonthat its pronounced skinirritant action necessitates extreme handlingcare to preventinjury to operating personnel. It

has also been reported that the ethoxymethylenemalonate should be of ahigh degree of purity and that useof impure ester led to deepdecoloration and low yields on cyclization steps.

The Dains formamidine synthesis (Dains, Ber. 35, 2496 [1902] Dains andBrown, JACS 31, 1148 [1909]) is given by the following equation in whichdiarylformamidines (3) are reacted with cyanomethylene compounds.

The usefulness of the above reaction is limited to cyanomethylenecompounds because of the secondary aminolysis of the reaction productsby Theicompleteness of the secondary reaction is 3 cned largely by thetemperature and the e of the reacting derivative. Thus, with c est r theamide formation is practically etoacetic ester 50-80% of the 1 thecarbethoxy group, while ester no amide formation occurs Brown, JACS 31,1148 [1909]). nvestigators have used the Dains resynthesizearylaminomethyleneinalonates of the type (i) under carefully controlledexperimental conditions even to the point of interrupting the reactionat about 40% conversion (Price and Roberts, JACS 68, 1255 [19%]; RobertsJ. Org. Chem. i l, 277 (1949); Fisher, USP 2,494,801 [l/l'Z/50l). Thecomplications due to the release of the arylarnine and the formation or"anilides of the class (4) is magnified considerably by the problems or"recovering and removing the starting materials.

Snyder and Jones (JACS 68, 1253 [1945]; US? have modified the Dainssynthesis by preparing the diarylfcrrnamidines (3) from ethylorthoformate and the arylarnine in the presence of the active methylenecompound thereby accomplishin a direct synthesis. Eowever, as in theDains reaction, the method was most successful with cyanoacetic ester.The reaction with malonic ester occurred readily, but the product wasnot the expected dicarboxylic ester but rather the correspondingmono-in-chloroanilide.

Inasmuch as a.-substituted-B-arylamineacrylates of the class of (l) and(2) are valuable intermediates in the preparation of the nuclearsubstitu'ted i-hydroXyouinolines, it is the object of the presentinvention to provide an improved process of preparing said compoundswhile avoiding the objectionable features and difiiculties noted above.

Other objects and advantages will become apparent from the followingdescription.

In carrying out the improved process a molecular equivalent of anN-arylforrnamidic acid ester and a molecular equivalent, in slightexcess, of a lower diallryl malonate, in the presence of a catalyticamount of an inorganic or organic base material under substantiallyanhydrous conditions, is heated either to reflux or at a temperatureranging from ell-140 C. for several hours, until condensation iscompleted. This usually takes from 20 to 35 hours. The lower alkylalcohol liberated during the condensation reaction as well as the natureof the coreactants and basic catalyst often determine the finalcondensation reaction is crature. Despite the initial temperature erpioyed, it will fall repeatedly as the lower alcohol is'forraed in thereaction vessel and will finally reach a definite steady temperaturewhich may range from 8@ll0 C. The basic catalyst .eutralized with anyacid, preferably with 3 molar hydrochloric acid and the reaction mixturesteam distilled to remove the lower alcohol and excess inalonic esterand unreacted N-arylformamid-ic acid esters. The final product isrecovered by either crystallization from ethanol, aqueous methanol,petroleum ether, or by solvent extraction with ether, benzene, toluene,and the like. The yield of the final product averages about 35-88%.

The N-arylformimidic acid esters employed in the foregoing condensationreaction are characteriz d by the following general formula:

The usefulness of the above reaction is limited wherein R represents alower alkyl, i. e., methyl, ethyl, propyl, isopropyl, cutyl, isobutyl,etc, and R1 represents a halogen, g., chlorine, bromine, iodine, a loweralley] of the same value as R, allrylamino, e. g., CH3NH, C2;- 5l-TH-,C3I'I'7NH-, C4I-I9li'lI, etc. aikoxy, e. niethexy, ethoxy, propoxy,isopropoxy, butoxy, isebutoizy, and the like.

Such acid esters are readily prepared in good yields by following theprocedure of Roberts (JACS ii, 3848 [1949]) which invo' es the acidcatalyzed reaction of arylainines and diaryliormamidines with ethylorthoforrnate or equivalent lower 1 alkyl orthoformate. lln1chlorophen5. 1- formarnidic acid esters and the process of preparingthe same are disclosed in my application Serial No. 264,351, filed oneven date, to which reference is made as the types of esters which maybe employed in the process of the present invention.

As examples of suitable arylamines, which may be employed in thepreparation of the aforestated N-arylformamidic acid esters, thefollowing may be mentioned:

Arylamines Anilline o-, p-, and m-Chloroaniline p-Toluidine m-Cumidinep-Methoxyaniline o-, m-, and p-Phenetidine N -arylformamidate EthylN-phenylformimidate Ethyl N-o-chlorophenylformimidate EthylN-m-chlorophenylformimidate Ethyl N-p-chlorophenylforrnimidate Ethyl N-p-tolylformimidate Ethyl N-m-cumylformimidate MethylN-p-methoxyphenylformimidate Ethyl N -o-phenetylformimidate Ethyl N-m-phenetylformimidate Ethyl N-p-phenetylformimidate The lower dialkylmalonates, which are condensed-with an N -ary1formimidic acid ester, maybe those, such as, for example, dimethyl, diethyl, dipropyl,diisopropyl, dibutyl malonates, and the like.

The base catalyst which may be employed in the condensation reaction isany one of the usual inorganic or organic base materials, such as sodiumand potassium salts of aliphatic acids, i. e., formic, acetic,propionic, butyric, etc, sodium and potassium allzozides, e. g., sodiumor potassium methylate or ethylate, etc, sodium or potassium carbonate,organic amine bases, trimethylamine, triethylaznine, pyridine,methylpyridine, ethylpyridine, piperidine, quinoline, benzyltrimethylammonium hydroxide, sodium or potassium phenolates, e. g., sodium orpotassium phenoxide, and the like.

The following examples illustrate in more detail how the improvedprocess is utilized in the preparation of the arylaminomethylenemalonicacid esters. It is to be understood that these examples are merelyillustrative and are not to be construed as being limitative.

Amixture. of 44 grams of diethyl malonate, 46 grams of ethylN-m-chlorophenylformimidate (boiling point of 95" C. at 3.5 mm., n1.5399, 114. 1.134) and- 1 ml. of piperidine was heated for 24 hours.The initial temperature employed was 130 C. and fell repeatedly asalcohol was formed in the reaction to reach a final temperature of 102C. The contents were subjected to steam distillation to remove theexcess malonic ester. The product was extracted with benzene, dried, andconcentrated. The yield of ethyl a-carbethoxy-p-m-chloroanilinoacrylatewas 65 grams or 87%. A small portion was recrystallized from low boilingpetroleum ether and gave a melting point of 55-56 C. which is identicalwith the melting point and mixed melting point with a sample prepared bythe method. of Price and Roberts (JACS 68, 1204 [1946]).

EXAMPLE II A mixture of 176 grams of diethyl malonate, 184 grams ofethyl N-m-chlorophenylformimidate and 2.7 grams of sodium methylate washeated at 93-96 C. for 24 hours. The contents were neutralized to litmuswith dilute hydrochloric acid and subjected to steam distillation. Theproduct was taken up in benzene, dried, and concentrated. The weight ofethyl a-carbethoxy- B-m-chlorcanilinoacrylate was 286 grams or 96%.

EXAMPLE III EXAMPLE IV cmo NHCH=O(COO 011m A mixture of 145 grams ofdimethyl malonate, 165 grams of methyl N-p-anisylformimidate and 2.7grams of sodium methylate was heated at 90-95 C. for 24 hours. Thecontents were neutralized to litmus with dilute hydrochloric acid andthen subjected to steam distillation. The product was taken up inbenzene, dried, and concentrated. The weight of methyla-carbomethoxy-B-(p-methoxyanilino) -acrylate obtained was 252 grams or95%.

EXAMPLEV NHCH=C-(OOOC4H0)2 A mixture of 238 grams of dibutyl malonate,

177 grams of ethyl N-p-ethylphenylformimidate, and. 4.7 grams ofanhydrous potassium acetate taken up. in toluene,

waseheated. underzreflux:at195e1Q5 fora 30*- hours. The.solutionewasmeutralized:and: steam. distilled'to removeexcess reactants.:The butyl: a.- carbobutoxy p.- .(p-ethylanilino) -acry1ate-was: dried,and concentrated. The yield was f :5. 51..

om; I I

The procedure of Example I was followed except that 5-2 grams ofdi-n-propyl malonate was used in place of the diethyl malonate and that48 grams of ethyl N-p-dimethylaminophenylformimidate was used in placeof ethyl N-m-chlorophenylformimidate. The yield of propyl acarbopropoxy,8 (p-dimethylanilino)-acrylate obtained was 82%.

EXAMPLE VII The procedure of Example II was followed with the exceptionthat 149 grams of ethyl N-mphenylformimidate was used in place of 184grams of N-m-chlorophenylformimidate. A yield of 94% of ethyla-carbethoxy-fl-anilinoacrylate was obtained.

From the foregoing examples, it is readily apparent that the processsteps of the present invention provide an improved method of preparingarylaminoethylenemalonates. The method avoids the difficulties of thepoor and. erratic synthesis and troublesome handling ofethoxymethylenemalonic ester. The intermediates, N-arylformimidic acidesters, are readily prepared and handled. Another significant feature ofthe process is that the presence of free amines is completely avoidedand the possibility for anilide formation by completing secondaryreactions is completely avoided. This overcomes a serious drawback topractically all of the arylaminoacrylate syntheses which suffer fromcontamination of such anilides. It is also to be noted that theinexpensive and commercially available lower dialkylmalonates is thereagent employed in excess and not the expensive and unavailableethoxymethylenemalonic ester of the Price synthesis. Moreover, theemployment of a basic catalyst contributes to the excellent yieldsobtained. The function of the basic catalyst is to promote the formationof an enolate anion from the malonic ester.

While I have disclosed the preferred embodiments of my invention, itwill be readily appreciated by those skilled in the art that manychanges and variations may be made therein without departing from thespirit thereof. The scope of the invention is to be limited solely bythe appended claims.

I claim:

1. The process of preparing arylaminomethylenemalonates selected fromthe class consisting of the following formulae:

and

7 8 wherein R represents a lower alkyl group, and 3. The processaccording to claim 1, wherein R1 represents .a member selected from theclass the lower dialkylmalonate is diethylmalonate. consisting .ofhalogen, lower alkyl, lower alkyl- 4. The process according to claim 1,wherein amino, and lower alkoxy radicals, which comthe lowerdialkylmalonate is dipropylmalonate.

prisesheatinga mixture of a loweralkyl 'N-aryl- 5 5- T e DI according toClaim 1, Wherein formimidate and a lower dialkyl lonate inthe the lowerdialkylmalonate is dibutylmalonate. presence of a basic catalyst,distilling the reaction mixture to remove unreacted. components, SAMUELGLICKMAN' and isolating the arylaminoethylenemalonate.

2. The process according to claim 1, wherein 10 the lowerdialkylmalonate is dimethylmalonate. No references cited.

1. THE PROCESS OF PREPARING ARYLAMINOMETHYLENEMALONATES SELECTED FROMTHE CLASS CONSISTING OF THE FOLLOWING FORMULAE: